Retinoid metabolism and its effects on the vasculature

Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.     

动脉粥样硬化中单核细胞膜流动性研究

为研究动脉粥样硬化中单核细胞膜流动性的变化,本实验选用20只新西兰白兔建立动物粥样硬化模型,提取模型组与对照组兔外周血中单核细胞,通过荧光漂白恢复技术检测单核细胞膜流动性,并结合动脉粥样硬化动物模型病理切片揭示其与动脉粥样硬化相关性。结果显示动物动脉粥样硬化模型建立成功,模型组单核细胞膜的荧光恢复率和扩散系数均低于对照组。本研究揭示了单核细胞细胞膜的流动性与动脉粥样硬化的发生有关,为今后深入探究单核细胞与动脉粥样硬化关系提供实验基础。     

Mouse models of experimental atherosclerosis.

Since 1992 the mouse has become an excellent model for experimental atherosclerosis research. Until 1992, the diet -- induced atherosclerosis mouse model has been used effectively, but the lesions tended to be small and were limited to early fatty-streak stage. This model was also criticized because of the toxicity and inflammatory responses due to the diet. In 1992 the first line of gene targeted animal models, namely apolipoprotein E -- knockout mice was developed. Of the genetically engineered models, the apoE -- deficient model is the only one that develops extensive atherosclerotic lesions on a chow diet. It is also the model in which the lesions have been characterized most thoroughly. The lesions develop into fibrous plaques; however, there is no evidence that plaque rupture occurs in this model. The LDL receptor - deficient model has elevated LDL levels, but no lesions, or only very small lesions, form on the chow diet, however, robust lesions do form on the western-type diet. The creation of apoE -- knockout mice has changed the face of atherosclerosis research.     

Role of reactive aldehyde in cardiovascular diseases

There is increasing evidence that aldehydes generated endogenously during the degradation process of biological molecules are involved in many of the pathophysiologies associated with cardiovasular diseases such as atherosclerosis and the long-term complications of diabetes. Major sources of reactive aldehydes in vivo are lipid peroxidation, glycation, and amino acid oxidation. Although the types of aldehydes are varied, the important aldehydes that can exert biological effects relevant to the pathobiology of oxidant injury are represented by 2-alkenals, 4-hydroxy-2-alkenals, and ketoaldehydes. These aldehydes exhibit facile reactivity with proteins, generating stable products at the end of a series of reactions. The protein-bound aldehydes can be detected as constituents not only in in vitro oxidized low-density lipoproteins but also in animal models of atherosclerosis and in human patients with increased risk factors or clinical manifestations of atherosclerosis, indicating that they could indeed be involved in the caldiovascular pathology. On the other hand, a number of reactive aldehydes have been implicated as inducers in generating intracellular oxidative stress and activation of stress signaling pathways, that integrate with other signaling pathways to control cellular responses to the extracellular stimuli.     

Role of extracellular retention of low density lipoproteins in atherosclerosis

The pathogenesis for atherosclerosis is still unclear, and several hypotheses have been articulated to explain the initiating events in atherogenesis. Although these hypotheses are by no means mutually exclusive, there is a growing body of recent evidence that has led to the concept that subendothelial retention of apolipoprotein B100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation. The present review assesses some of the studies that support this concept.     

Study of the interaction of the C-reactive protein monomer with the U937 monocyte

C-reactive protein (CRP) has two structurally distinct isoforms, the CRP pentamer and the CRP monomer. A role for the CRP monomer in atherosclerosis is emerging, but the underlying mechanisms are only beginning to be understood. Monocytes are an important contributor to atherosclerosis, and foam cell formation is the hallmark of atherogenesis. However, whether the CRP monomer can directly interact with the monocytes and modulate their responses remains unknown. Furthermore, although FcγRIII (CD16) has been identified as the receptor for the CRP monomer on neutrophils, its role in mediating the CRP monomer’s biological effects in other cell types has been questioned. In this study, we investigated the interaction of the CRP monomer with the monocytes using the U937 monocytic cell line. The CRP monomer specifically binds to U937 cells. This binding is unique in that it is independent of FcγRs and insensitive to protease digestion of the cell surface proteins. Further assays revealed that the CRP monomer directly incorporates into the plasma membrane. Interestingly, the presence of the CRP monomer efficiently retards oxidized low-density lipoprotein-induced foam cell formation of PMA-differentiated U937 macrophages and peripheral blood monocytic cell-derived macrophages. These findings provide additional evidence for the notion that the CRP monomer is an active CRP isoform that plays a role in atherogenesis via the direct modulation of the behavior of the monocytes.     

Periodontal infections and atherosclerosis: mere associations?

PURPOSE OF REVIEW: Several lines of evidence from the last few decades suggest that periodontitis is an important risk factor for cardiovascular diseases. In this review we discuss the recent findings on the systemic effects of periodontitis, which may contribute to the pathogenesis of atherosclerosis, with a special emphasis on lipoproteins. RECENT FINDINGS: In addition to the epidemiological studies exploring the direct or indirect relationship between clinical periodontitis and cardiovascular diseases, studies utilizing serology, animal models, cell cultures, and biochemistry of lipoproteins have been published. Local infection in the periodontal pockets triggers a systemic inflammatory response releasing inflammatory mediators and awakens a strong immune response against periodontal pathogens. Elevated systemic antibody levels especially to Porphyromonas gingivalis are associated with an increased risk for atherosclerosis. Periodontitis is also accompanied by proatherogenic changes in both low and high density lipoproteins, which lead to enhanced cholesteryl ester uptake by and reduced cholesterol efflux from macrophages. Vesicles and lipopolysaccharide isolated from P. gingivalis activate macrophages to convert into foam cells. Moreover, animal studies have demonstrated that infection by P. gingivalis enhances progression of atherosclerosis. SUMMARY: Recent studies have clarified the mechanisms by which periodontitis may contribute to the development of atherosclerosis. Serological, animal, and cell culture studies provide evidence that infection by P. gingivalis may promote atherosclerosis. The influence of periodontitis on lipoprotein metabolism has emerged as a new, important factor. Recent studies provide experimental proof that periodontitis may predispose to atherosclerosis.     

Role of Nrf2 in the pathogenesis of atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the vascular arterial walls. A number of studies have revealed the biological and genetic bases of atherosclerosis, and over 100 genes influence atherosclerosis development. Nrf2 plays an important role in oxidative stress response and drug metabolism, but the Nrf2 signaling pathway is closely associated with atherosclerosis development. During atherosclerosis progression, Nrf2 signaling modulates many physiological and pathophysiological processes, such as lipid homeostasis regulation, foam cell formation, macrophage polarization, redox regulation and inflammation. Interestingly, Nrf2 exhibits both pro- and anti-atherogenic effects in experimental animal models. These observations make the Nrf2 pathway a promising target to prevent atherosclerosis.     

Occurrence,properties, and applications of feruloyl esterases

Feruloyl esterases hydrolyze the ester linkages of ferulic and diferulic acids present in plant cell walls. This interesting group of enzymes also has a potentially broad range of applications in the pharmaceutical and agri-food industries. An overview of the current knowledge of fungal feruloyl esterases focusing on the diverse of substrate specificity and potential applications is presented in this review. Furthermore, biological functions of ferulic acid are discussed.     

Enhancement of cheese flavors with microbial esterases

The characteristic flavor of hard Italian cheeses is associated with the presence of fatty acids, particularly butyric acid, liberated from milk fat during the ripening process. To ensure proper development and control of flavor, animal pregastric esterases or lipases are routinely added to the milk before coagulation of the curd. Such esterases are also used to generate flavor in enzyme modified cheese and other dairy products. Esterases from microbial sources have been investigated as agents to enhance flavor in cheese. We have found that an esterase from Mucor miehei exhibits the type of lipolytic activity needed for this application. Romano and fontina cheeses of excellent quality have been prepared by the use of this esterase. It has also been used successfully in the preparation of enzyme modified cheese, and, in turn, processed American cheese.     

Tea polyphenols, their biological effects and potential molecular targets

Tea is the most popular beverage in the world, second only to water. Tea contains an infusion of the leaves from the Camellia sinensis plant rich in polyphenolic compounds known as catechins, the most abundant of which is (-)-EGCG. Although tea has been consumed for centuries, it has only recently been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. The results of several investigations indicate that green tea consumption may be of modest benefit in reducing the plasma concentration of cholesterol and preventing atherosclerosis. Additionally, the cancer-preventive effects of green tea are widely supported by results from epidemiological, cell culture, animal and clinical studies. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols were shown to affect several biological pathways, including growth factor-mediated pathway, the mitogen-activated protein (MAP) kinase-dependent pathway, and ubiquitin/proteasome degradation pathways. Various animal studies have revealed that treatment with green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Recently, phase I and II clinical trials have been conducted to explore the anticancer effects of green tea in humans. A major challenge of cancer prevention is to integrate new molecular findings into clinical practice. Therefore, identification of more molecular targets and biomarkers for tea polyphenols is essential for improving the design of green tea trials and will greatly assist in a better understanding of the mechanisms underlying its anti-cancer activity.     

Creating animal models,why not use the Chinese tree shrew (Tupaia belangeri chinensis)?

The Chinese tree shrew (Tupaia belangeri chinensis),a squirrel-like and rat-sized mammal,has a wide distribution in Southeast Asia,South and Southwest China and has many unique characteristics that make it suitable for use as an experimental animal.There have been many studies using the tree shrew (Tupaia belangen) aimed at increasing our understanding of fundamental biological mechanisms and for the modeling of human diseases and therapeutic responses.The recent release of a publicly available annotated genome sequence of the Chinese tree shrew and its genome database (www.treeshrewdb.org) has offered a solid base from which it is possible to elucidate the basic biological properties and create animal models using this species.The extensive characterization of key factors and signaling pathways in the immune and nervous systems has shown that tree shrews possess both conserved and unique features relative to primates.Hitherto,the tree shrew has been successfully used to create animal models for myopia,depression,breast cancer,alcohol-induced or non-alcoholic fatty liver diseases,herpes simplex virus type 1 (HSV-1) and hepatitis C virus (HCV) infections,to name a few.The recent successful genetic manipulation of the tree shrew has opened a new avenue for the wider usage of this animal in biomedical research.In this opinion paper,I attempt to summarize the recent research advances that have used the Chinese tree shrew,with a focus on the new knowledge obtained by using the biological properties identified using the tree shrew genome,a proposal for the genome-based approach for creating animal models,and the genetic manipulation of the tree shrew.With more studies using this species and the application of cutting-edge gene editing techniques,the tree shrew will continue to be under the spot light as a viable animal model for investigating the basis of many different human diseases.     

The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo

The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis. We found that, compared with p53+/+/apoE-/- mice, p53-/-/apoE-/- mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53-/-/apoE-/- mice had a significant (approximately 280%) increase in cell proliferation rate and an insignificant (approximately 180%) increase in apoptosis compared with those in p53+/+/apoE-/- mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.     

Formal agent-based modelling of intracellular chemical interactions

Individual-based or agent-based models have proved useful in a variety of different biological contexts. This paper presents an agent-based model using a formal computational modelling approach to model a crucial biological system--the intracellular NF-kappaB signalling pathway. The pathway is vital to immune response regulation, and is fundamental to basic survival in a range of species. Alterations in pathway regulation underlie many diseases, including atherosclerosis and arthritis. Our modelling of individual molecules, receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based approaches. The model has been validated with data obtained from single cell experimental analysis.     

Modulation of PPARgamma activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis

The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a member of the ligand-activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARgamma, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin-sensitizing activities as well as tissue selectivity of PPARgamma activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARgamma activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti-atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARgamma agonists can be potentially employed for the treatment of atherosclerosis in general population.     

On the Use of a Simple Physical System Analogy to Study Robustness Features in Animal Sciences

Environmental perturbations can affect the health, welfare, and fitness of animals. Being able to characterize and phenotype adaptive capacity is therefore of growing scientific concern in animal ecology and in animal production sciences. Terms borrowed from physics are commonly used to describe adaptive responses of animals facing an environmental perturbation, but no quantitative characterization of these responses has been made. Modeling the dynamic responses to an acute challenge was used in this study to facilitate the characterization of adaptive capacity and therefore robustness. A simple model based on a spring and damper was developed to simulate the dynamic responses of animals facing an acute challenge. The parameters characterizing the spring and the damper can be interpreted in terms of stiffness and resistance to the change of the system. The model was tested on physiological and behavioral responses of rainbow trout facing an acute confinement challenge. The model has proven to properly fit the different responses measured in this study and to quantitatively describe the different temporal patterns for each statistical individual in the study. It provides therefore a new way to explicitly describe, analyze and compare responses of individuals facing an acute perturbation. This study suggests that such physical models may be usefully applied to characterize robustness in many other biological systems.     

Induction of CD1-restricted immune responses in guinea pigs by immunization with mycobacterial lipid antigens

Group 1 CD1 molecules have been shown to present lipid and glycolipid Ags of mycobacteria to human T cells. However, a suitable animal model for the investigation of this component of antimycobacterial immunity has not yet been established. Previously, we found that guinea pigs express multiple isoforms of group 1 CD1 proteins that are homologous to human CD1b and CD1c. In this study, we show that CD1-restricted T cell responses can be generated in guinea pigs following immunization with lipid Ags from Mycobacterium tuberculosis. Splenic T cells from lipid Ag-immunized guinea pigs showed strong proliferative responses to total lipid Ags and partially purified glycolipid fractions from M. tuberculosis. These lipid Ag-reactive T cells were enriched in CD4-negative T cell fractions and showed cytotoxic activity against CD1-expressing guinea pig bone marrow-derived dendritic cells pulsed with M. tuberculosis lipid Ags. Using guinea pig cell lines transfected with individual CD1 isoforms as target cells in cytotoxic T cell assays, we found that guinea pig CD1b and CD1c molecules presented M. tuberculosis glycolipid Ags to T cells raised by mycobacterial lipid immunization. These results were confirmed using a T cell line derived from M. tuberculosis lipid Ag-immunized guinea pigs, which also showed CD1-restricted responses and cytolytic activity. Our results demonstrate that CD1-restricted responses against microbial glycolipid Ags can be generated in vivo by specific immunization and provide support for the use of the guinea pig as a relevant small animal model for the study of CD1-restricted immune responses to mycobacterial pathogens.     

Toll-like receptor 4 in atherosclerosis

Toll-like receptor 4 (TLR4) is key regulators of both innate and adaptive immune responses. TLR4 recognizes pathogen-associated molecular patterns (PAMPs) and activates the inflammatory cells. The function of TLR4 in atherosclerosis has been investigated in mouse knockout studies and epidemiological studies of human TLR4 polymorphisms. These studies have shown that TLR4 function affects the initiation and progression of atherosclerosis. This article reviews the biological functions and clinical implications of TLR4 in atherosclerosis.     

Assignment of the pig apolipoprotein B locus (APOB) to chromosome region 3q24-qter

The locus for apolipoprotein-B (APOB) has been chromosomally assigned in swine by in situ hybridization of a genomic probe to metaphase chromosomes. As expected based on the observation of extensive linkage conservation and based on the previous assignment of the malate dehydrogenase locus (MDH1) in swine, APOB maps to chromosome 3, specifically to region 3q24-qter. Variations at APOB may represent both in humans and in swine risk factors for hypercholesterolaemia and atherosclerosis. Evidence presented here that the human and porcine APOB occupy evolutionarily conserved chromosome regions provides a basis for using the pig as an animal model to study the APOB associated atherosclerosis risk.     

A lead phthalocyanin method for the demonstration of acid hydrolases in plant and animal tissues

Summary A new method of synthesis of the lead phthalocyanin and the chemical properties of its diazotate are described. The use of this reagent for high resolution studies of the localization of intra- and extralysosomal acid phosphatases and esterases in plant and animal cells has been assessed.